The primary focus of this application is the total synthesis of complex, biomedically significant natural products constituted of tetrahydroisoquinolines. The synthetic chemistry that will be developed shall be utilized to prepare analogues of the natural substances as biological and mechanistic probes. This proposal is primarily hypothesis-driven, and extensively employs new synthetic methodologies developed in this laboratory for the construction of such agents. The specific aims of this program are to study the interaction of the natural antitumor antibiotics and mechanistically inspired synthetic analogs, including ecteinascidin 743 (Et-743), saframycin A, jorumycin, tetrazomine, lemonomycin, renieramycin H and the bioxalomycins with cellular nucleic acids. The DNA alkylating capacity of these drugs compared with their ability to cause oxidative damage to nucleic acids will be explored. The synthesis of members of this class of antitumor drugs will continue to be developed with the objective of harnessing the synthetic methodology developed to make new, less toxic, more selective and more potent antitumor drugs. In addition, the tools of synthesis will be exploited to synthesize mechanistic probes for the interaction of these substances with cellular nucleic acids and oncoproteins that bind to cellular nucleic acids.